An important aspect of the administration of drugs in conventional forms is the fluctuation between high and low plasma concentration of the drug in the period between the administration of two successive doses. In fact, if the drug is too rapidly absorbed, excessive plasma levels may be attained, leading to undesirable and even toxic side effects. On the other hand, drugs possessing a short half-life are eliminated too rapidly and require therefore frequent administrations. In both cases the patient must be careful because particular attention and constancy in the administration is required during therapy and such conditions can not always be easily obtained. Many efforts have been made to formulate pharmaceutical preparations able to protract in time the activity of the drug in the body at optimum plasma levels, reducing the number of administrations and thus improving the response of the patient to the treatment.
The preparation of pharmaceutical compositions intended to supply a gradual and controlled release in time of the active ingredient is well known in the pharmaceutical technology field. Systems are known comprising tablets, capsules, microcapsules, microspheres and formulations in general in which the active ingredient is released gradually by various means.
It is also known that oral administration is by far the most frequently employed in therapy and the most appreciated by the patient, particularly when repeated administrations are otherwise necessary. Among formulations for oral administration, the liquid ones present the advantage of being easily adaptable to the patient in dosage and better accepted by the patient, particularly by children and the elderly. For this reason a liquid controlled release formulation is more advantageous compared to a corresponding controlled release solid formulation.
In the preparation of controlled release liquid pharmaceutical compositions several problems may be encountered. One problem is that the actual controlled release forms must be of such a size to be easily suspended and kept in suspension in the liquid vehicle. Furthermore, poor or non-homogeneous distribution in the vehicle is to be avoided as far as possible, and it is also preferable to avoid the unpleasant sensation which may be present upon ingestion of a suspension containing a solid of coarse particles (sand effect). This problem may be avoided by suitably reducing the size of the particles to be suspended. On the other hand, the use of reduced size particles, increasing the surface area available for diffusion, makes it difficult to obtain a constant and protracted control of release, as is possible with particles having larger dimensions.
A further problem is the difficulty of obtaining controlled release liquid preparations able to maintain for a long period the release characteristics of the pharmaceutical compound contained. The solution of these problems is commercially and therapeutically important both for the necessity of having ready-to-use liquid dosage formulations as far as possible stable in time, and for having liquid formulations which, prepared at the moment of use, will remain stable for a long time once the dispersion of the therapeutic agent in the dosage liquid has taken place.
All the above mentioned difficulties may explain why only a few controlled release liquid systems are known, and among them .only one is actually available commercially. Examples of known controlled release liquid formulations are found in the following patents: BE903540, WO85/03000, WO 87/07833, U.S. Pat. Nos 4,221,778 and 4,717,713.
The necessity is felt therefore, for a system which allows the administration of substances in a liquid oral dosage form in such a way that the release in time of the substances may be effected in the best possible way according to pre-established schedules. Such a system should be adjustable according to the particular therapeutic characteristics of the active ingredient to be administered; should possess homogeneity characteristic such as to allow a correct dosage; and should maintain its characteristics in the selected vehicle for a long period of time even after the beginning of the treatment.